Abstract: AIM To study the effect of U50,488H, a selective agonist of kappa-opioid receptor, on vascular endothelial functions in rats with hyperlipidemia. METHODS Adult SD rats were fed with normal or high-fat diet for 14 weeks, respectively. U50,488H and normal saline (NS) were intraperitoneally injected on alternate days. Blood samples were harvested from inferior vena cava after anesthesia and total cholesterol and low-density lipoprotein were then detected. Ultrastructural changes of artery endothelial cells and smooth muscle cells were observed with transmission electron microscopy (TEM). The aorta was separated to observe the vasorelaxation reaction of thoracic aorta in response to acetylcholine (ACh), an endothelium-dependent vasodilating agent and SNAP, an endothelial-independent vasodilatation agent. RESULTS Endothelial structures were impaired under electron microscope in rats fed with a high-fat diet. There was a significant rise in blood lipid levels and a significantly lower thoracic aorta response to ACh. With treatment of U50,488H, endothelial structure and functions were significantly improved compared with those in high-fat diet group. The effects of U50,488H were blocked by nor-BNI, a selective kappa-opioid receptor antagonist. CONCLUSION Kappa-opioid receptor stimulation with U50,488H improves endothelial structure and functions in rats with hyperlipidemia.